Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo

作者：Popovici Muller Janeta^*; Saunders Jeffrey O; Salituro Francesco G; Travins Jeremy M; Yan Shunqi; Zhao Fang; Gross Stefan; Dang Lenny; Yen Katharine E; Yang Hua; Straley Kimberly S; Jin Shengfang; Kunii Kaiko; Fantin Valeria R; Zhang Shunan; Pan Qiongqun; Shi Derek; Biller Scott A; Su Shinsan M

来源：ACS Medicinal Chemistry Letters, 2012, 3(10): 850-855.

DOI：10.1021/ml300225h

• Mutant IDH1
• tumor 2-HG
• R132H IDH1 inhibitors

Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and similar to 90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration.

• 出版日期2012-10